Compounds based on the ergoline ring system: ##SPC1##
Have a surprising variety of pharmaceutical activities. For example, lysergic and isolysergic acid are 8-carboxy-6-methyl-9-ergolenes. The amides of lysergic acid, many of which have valuable and unique pharmacologic properties, include the naturally occurring oxytocic alkaloids -- ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, ergotamine, etc. -- and synthetic oxytocics such as methergine as well as the synthetic hallucinogen -- lysergic acid diethylamide or LSD. The amides of 6-methyl-8-carboxyergoline, known generically as dihydroergot alkaloids, are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves. Recently, it has been found by Clemens, Semonsky, Meites, and their various co-workers that many ergot-related drugs have activity as prolactin inhibitors including ergocornine, dihydroergocornine, 2-bromo-.alpha.-ergokryptine and d-6-methyl-8-cyanomethylergoline. References embodying some of the newer findings in the field of ergoline chemistry are the following: Nagasawa and Meites, Proc. Soc. Exp't'l. Biol. Med, 135, 469 (1970); Lutterbeck et al., Brit. Med. J., 228, (July 24, 1971); Heuson et al., Europ. J. Cancer, 353 (1970); Coll. Czech, Chem. Commun., 33, 577 (1968); Nature, 221, 666 (1969); Seda et al., J. Reprod. Fert., 24, 263 (1971); Mantle and Finn, id, 441; Semonsky and co-workers, Coll. Czech. Chem. Comm., 36, 2200 (1971); Schaar and Clemens, Endocr., 90, 285-8 (1972); Clemens and Schaar, Proc. Soc. Exp. Biol Med., 139, 659-662 (1972) and Sweeney, Clemens, Kornfeld and Poore, 64th Annual Meeting, American Association Cancer Research, April 1973. Recently issued patents in the field of ergoline derivatives or lysergic acid derivatives include the following: U.S. Pat. Nos. 3,704,233, 3,709,891, 3,585,201, 3,666,762, 3,586,683, 3,717,640, and 3,592,816.
A number of non-peptide indole alkaloids have been found in fungus cultures grown on Elymus nollis and other related grasses. These non-peptide alkaloids include chanoclavine, agroclavine, elymoclavine, and penniclavine. Of particular interest are agroclavine, an 8-methyl-8-ergolene; elymoclavine, an 8-hydroxymethyl-8-ergolene, and penniclavine, an 8-hydroxymethyl-8-hydroxy-9-ergolene. These non-peptide alkoloids have been shown to have potent rat prolactin inhibiting activity comparable to that found with the peptide alkaloid, ergocornine.
D-6,8-dimethyl-9-ergolene has been prepared as one of seven related products by the reduction of elymoclavine with sodium in n-butanol according to Yamatodani and Abe, Bull. Agr. Soc. Japan, 20, 95 (1956). Descarboxylysergic acid has not hitherto been described, and there is no method known in the art for removing the 8-methyl group from D-6,8-dimethyl-9-ergolene to produce descarboxylysergic acid.